Brain delivering RNA-based therapeutic strategies by targeting mTOR pathway for axon regeneration after central nervous system injury

NEURAL REGENERATION RESEARCH, 2022 · DOI: 10.4103/1673-5374.335830 · Published: October 1, 2022

Pharmacology Neurology Regenerative Medicine & Stem Cells

Simple Explanation

Injuries to the central nervous system (CNS) often result in permanent disabilities because adult CNS neurons exhibit limited axon regeneration. The brain has an intrinsic capability of recovering itself after injury. The mechanistic target of rapamycin (mTOR) signaling is one of the most crucial intrinsic regenerative pathways that drive axonal regeneration and sprouting in various CNS injuries. RNA-based therapeutics are suitable for blocking key mTOR signaling components such as phosphatase and tensin homolog (PTEN) and have attracted substantial attention recently.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Review

Key Findings

1
mTOR signaling is the intrinsic axon regenerative pathway, and its reactivation can promote axon regeneration after adult CNS injury.
2
Reactivation of the mTOR pathway can promote regrowth of dendrites and synaptogenesis, and restores circuit function after traumatic CNS injury as well as in neurodegenerative diseases.
3
Upregulation of mTOR pathway activity is a promising strategy for promoting axon regeneration and sprouting after stroke.

Research Summary

This review discusses the critical roles of the mTOR pathway in axon regeneration in different types of CNS injury and demonstrates that the reactivation of this regenerative pathway can be achieved by blocking key mTOR signaling components such as PTEN. The review proposes the clinical application of RNA-mediated therapies in combination with brain-targeted drug delivery against mTOR signaling components as an effective therapeutic strategy to enhance axonal regeneration and functional recovery after CNS injury. Judicious design in formulation and particles using nanotechnology could be a promising direction for developing the next generation of RNA therapy for the treatment of CNS injury.

Practical Implications

Therapeutic Target Identification

Identifies mTOR pathway, particularly PTEN, as a promising therapeutic target for promoting axon regeneration after CNS injuries.

RNA-based Therapeutic Strategies

Highlights the potential of RNA-based therapeutics, such as antisense oligonucleotides, for modulating mTOR signaling components to enhance neural repair.

Drug Delivery Innovations

Emphasizes the importance of developing effective brain-targeted drug delivery systems, including nanoparticle technology, to facilitate clinical application of RNA-based therapies.

Study Limitations

1
Challenges in delivering RNA therapeutics to the brain due to the blood-brain barrier.
2
Potential limitations of targeting the mTOR pathway, such as effects on brain development and the risk of oncogenesis.
3
The need for transient PTEN knockdown to control the optimal effect on neural repair without causing undesirable effects.

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